2.1 Recommended Dosage

2.2 Instructions for Intravenous Administration

• Palonosetron HCl Injection is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/mL).
• Do not mix Palonosetron HCl Injection with other drugs.
• Flush the infusion line with normal saline before and after administration of Palonosetron HCl Injection.
• Inspect Palonosetron HCl Injection visually for particulate matter and discoloration before administration.
• Discard unused portion.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of Palonosetron HCl Injection [see Adverse Reactions (6.2)]. These reactions occurred in patients with or without known hypersensitivity to other 5-HT3 receptor antagonists. If hypersensitivity reactions occur, discontinue Palonosetron HCl Injection and initiate appropriate medical treatment. Do not reinitiate Palonosetron HCl Injection in patients who have previously experienced symptoms of hypersensitivity [see Contraindications (4)].

5.2 Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g. agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of Palonosetron HCl Injection and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Palonosetron HCl Injection and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Palonosetron HCl Injection is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of palonosetron HCl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria, anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1)]
• Injection site reactions: including burning, induration, discomfort and pain

7.1 Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue Palonosetron HCl Injection and initiate supportive treatment [see Warnings and Precautions (5.2)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

Of the 1374 adult cancer patients in clinical studies of intravenously administered palonosetron HCl, 316 (23%) were 65 years and over, while 71 (5%) were at least 75 years and over. Of the 1520 adult patients in clinical studies of intravenously administered palonosetron HCl, 73 (5%) were at least 65 years old [see Clinical Studies (14.1, 14.3)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity in some older individuals cannot be ruled out. Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients 65 years of age and older compared to younger patients [see Clinical Pharmacology (12.3)]. No dose adjustment is required for geriatric patients.

12.1 Mechanism of Action

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.

Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

After intravenous dosing of palonosetron HCl in healthy subjects and cancer patients, an initial decline in palonosetron plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0–∞) are generally dose-proportional over the dose range of 0.3 to 90 mcg/kg in healthy subjects and in cancer patients. Following a single intravenous dose of palonosetron HCl at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9 h∙mcg/L.

Following intravenous administration of Palonosetron HCl Injection 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42±34%. Following intravenous administration of palonosetron injection 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%.

After intravenous dosing of Palonosetron HCl Injection in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron HCl at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289 times the human exposure (AUC= 29.8 h∙mcg/L) at the recommended intravenous dose of 0.25 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.

Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test.

Palonosetron HCl at oral doses up to 60 mg/kg/day (about 1894 times the recommended human intravenous dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

14.1 Prevention of Nausea and Vomiting Associated with MEC and HEC in Adults

Efficacy of a single intravenous dose of Palonosetron HCl Injection in preventing acute and delayed nausea and vomiting associated with MEC or HEC were studied in 4 trials. In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy. The safety and efficacy of Palonosetron HCl Injection in repeated courses of chemotherapy was also assessed.

Efficacy Results

Studies 1, 2 and 3 show that Palonosetron HCl Injection was effective in the prevention of nausea and vomiting associated with initial and repeat courses of MEC and HEC in the acute phase (0 to 24 hours) [Table 5]. Clinical superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute phase. In Study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly.

Studies 1 and 2 show that Palonosetron HCl Injection was effective in the prevention of nausea and vomiting associated with initial and repeat course of MEC in the delayed phase (24 to 120 hours) [Table 6] and overall phase (0 to 120 hours) [Table 7].

Table 5: Prevention of Acute Nausea and Vomiting (0 to 24 Hours) in Adults with Nausea and Vomiting Associated with MEC or HEC in Studies 1, 2 and 3: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher's exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron HCl injection and comparator.
Chemotherapy	Study	Treatment Group	N*	% with Complete Response	p-value†	97.5% Confidence Interval Palonosetron HCl Injection minus Comparator‡
Moderately Emetogenic	1	Palonosetron HCl Injection 0.25 mg intravenously	189	81	0.009
		Ondansetron 32 mg intravenously	185	69
	2	Palonosetron HCl Injection 0.25 mg intravenously	189	63	NS
		Dolasetron 100 mg intravenously	191	53
Highly Emetogenic	3	Palonosetron HCl Injection 0.25 mg intravenously	223	59	NS
		Ondansetron 32 mg intravenously	221	57

Table 6: Prevention of Delayed Nausea and Vomiting (24 to 120 Hours) Associated with MEC in Adults in Studies 1 and 2: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher's exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron HCl injection and comparator. § Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
Chemotherapy	Study	Treatment Group	N*	% with Complete Response	p-value†	97.5% Confidence Interval Palonosetron HCl Injection minus Comparator‡
Moderately Emetogenic	1	Palonosetron HCl Injection 0.25 mg intravenously	189	74	<0.001
		Ondansetron 32 mg intravenously §	185	55
	2	Palonosetron HCl Injection 0.25 mg intravenously	189	54	0.004
		Dolasetron 100 mg intravenously	191	39

Table 7: Prevention of Overall Nausea and Vomiting (0 to 120 Hours) Associated with MEC in Adults in Studies 1 and 2: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher's exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron HCl Injection and comparator. § Ondansetron 32 mg intravenously was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
Chemotherapy	Study	Treatment Group	N*	% with Complete Response	p-value†	97.5% Confidence Interval Palonosetron HCl Injection minus Comparator‡
Moderately Emetogenic	1	Palonosetron HCl Injection 0.25 mg intravenously	189	69	<0.001
		Ondansetron 32 mg intravenously §	185	50
	2	Palonosetron HCl Injection 0.25 mg intravenously	189	46	0.021
		Dolasetron 100 mg intravenously	191	34

14.2 Prevention of Nausea and Vomiting Associated with Emetogenic Chemotherapy, Including HEC in Pediatric Patients

One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients. The total population (N = 327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of Palonosetron HCl Injection 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron injection) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hours after the first dose of ondansetron, with a maximum total dose of 32 mg). Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1,500 mg/m2), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.

Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of intravenous Palonosetron HCl Injection compared to intravenous ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous Palonosetron HCl Injection minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.

14.3 Prevention of Postoperative Nausea and Vomiting in Adults

In a multicenter, randomized, stratified, double-blind, parallel-group, clinical trial, Palonosetron HCl Injection was compared to placebo for PONV in 546 patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. The trial was conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of PONV and/or motion sickness.

Patients were randomized to receive a single dose of Palonosetron HCl Injection 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia. Antiemetic activity of palonosetron was evaluated during the 0 to 72-hour time period after surgery.

Of the 138 patients treated with palonosetron injection 0.075 mg and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers. As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian. The age of patients ranged from 21 to 74 years, with a mean age of 38 years. Three patients were greater than 65 years of age.

Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in 0 to 24 hours and 24 to 72 hours postoperatively.

  Secondary efficacy endpoints included:

• Complete Response (CR) 0 to 48 hours and 0 to 72 hours
• Complete Control (CC) defined as CR and no more than mild nausea
• Severity of nausea (none, mild, moderate, severe)

The primary hypothesis was that at least one of the three palonosetron doses were superior to placebo.

Complete Response Rates for palonosetron injection 0.075 mg and placebo in this trial are described in Table 9.

Palonosetron HCl Injection as a single dose of 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that Palonosetron HCl Injection 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.

A randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate Palonosetron HCl Injection for PONV following abdominal or vaginal hysterectomy. Five intravenous doses (0.1, 0.3, 1.0, 3.0 and 30 mcg/kg) were evaluated in a total of 381 intent-to-treat patients. The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery. The lowest effective dose was Palonosetron HCl Injection 1 mcg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004 and significantly reduced the severity of nausea versus placebo, p=0.009.

Storage

• Store at controlled temperature of 20 to 25°C (68 to 77°F). Excursions permitted to 15 to 30°C (59 to 86°F).
• Protect from freezing.
• Protect from light.

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients with or without known hypersensitivity to other 5-HT3 receptor antagonists. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur with administration of Palonosetron HCl Injection [see Warnings and Precautions (5.1)].

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of Palonosetron HCl Injection and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions (5.2)].